CDK12 mediated transcriptional regulation in U2OS cells
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA454480 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR7089370_1.fastq.gz | Fastqsanger.gz | |||
| SRR7089370_2.fastq.gz | Fastqsanger.gz | |||
| SRR7089380_1.fastq.gz | Fastqsanger.gz | |||
| SRR7089380_2.fastq.gz | Fastqsanger.gz | |||
| SRR7089390_1.fastq.gz | Fastqsanger.gz |
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Project description:While activation of canonical NF-κB signaling through the IKK complex is well studied, few regulators of NIK-dependent non-canonical p52 nuclear translocation have been identified. We discovered a novel role for cyclin dependent kinase 12 (CDK12) in transcriptionally regulating the non-canonical NF-κB pathway. High-content phenotypic screening identified a novel compound, 919278, which inhibits lymphotoxin β receptor (LTβR)- and FN14-dependent p52 nuclear translocation, but not TNFα receptor (TNFR)-mediated, canonical NF-κB p65 nuclear translocation. Chemoproteomics identified cyclin dependent kinase 12 (CDK12) as the target of 919278. CDK12 inhibition by 919278, THZ1, or siRNA knock down all affect similar global transcriptional changes and prevent LTβR and FN14-dependent MAP3K14 (NIK) mRNA induction and subsequent protein accumulation. In addition, 919278 and THZ1 treatment reduce RNA Pol II CTD phosphorylation. This powerful approach of coupling a phenotypic screen with chemoproteomics revealed a novel regulatory pathway of the non-canonical NF-κB pathway that could serve as a therapeutic target in autoimmunity and cancer.
2018-07-31 | GSE113926 | GEO
Project description:Targeting CDK12-mediated transcription regulation in anaplastic thyroid carcinoma
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Project description:Anaplastic thyroid carcinoma (ATC) is the most aggressive type of thyroid cancer, with no effective treatment available. Identification of new anti-ATC drugs represents an urgent need. In this study, we find that ATC cells are highly sensitive to THZ531, a potent inhibitor of the transcriptional cyclin-dependent kinase (CDK), CDK12. Cell-based assays demonstrate that CDK12 inhibition significantly impedes cell cycle progression, induces apoptotic cell death, and impairs colony formation in ATC cells. THZ531 causes a loss of elongating RNA polymerase II and suppresses gene expression in ATC cells. An integrative analysis of gene expression profiles and super-enhancer landscape, combining with functional assays, leads to the discovery of two new ATC cancer genes, ZC3H4 and NEMP1. Furthermore, CDK12 inhibition enhances the sensitivity of ATC cells to doxorubicin-mediated chemotherapy. Thus, these findings indicate that CDK12 is a potential therapeutic target for ATC treatment and its inhibition may help to overcome the chemoresistance in patients with ATC
2022-09-19 | GSE137697 | GEO
Project description:Anaplastic thyroid carcinoma (ATC) is the most aggressive type of thyroid cancer, with no effective treatment available. Identification of new anti-ATC drugs represents an urgent need. In this study, we find that ATC cells are highly sensitive to THZ531, a potent inhibitor of the transcriptional cyclin-dependent kinase (CDK), CDK12. Cell-based assays demonstrate that CDK12 inhibition significantly impedes cell cycle progression, induces apoptotic cell death, and impairs colony formation in ATC cells. THZ531 causes a loss of elongating RNA polymerase II and suppresses gene expression in ATC cells. An integrative analysis of gene expression profiles and super-enhancer landscape, combining with functional assays, leads to the discovery of two new ATC cancer genes, ZC3H4 and NEMP1. Furthermore, CDK12 inhibition enhances the sensitivity of ATC cells to doxorubicin-mediated chemotherapy. Thus, these findings indicate that CDK12 is a potential therapeutic target for ATC treatment and its inhibition may help to overcome the chemoresistance in patients with ATC
2022-09-19 | GSE137696 | GEO
Project description:Targeting CDK12-mediated transcription regulation in anaplastic thyroid carcinoma [RNA-seq]
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Project description:Targeting CDK12-mediated transcription regulation in anaplastic thyroid carcinoma [ChIP-seq]
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Project description:We describe the epigenetic profiling of the H3K9me2 and HP1a in Drosophila third instar larvae before and after CDK12 depletion by RNA interference (RNAi). Here we show that CDK12 regulates heterochromatin dynamics in Drosophila chromosomes. Depletion of CDK12 induces the increased HP1a and H3K9me2 binding profile on the coding region of euchromatic genes, with the X chromosome being the most affected. These results are consistent with the polytene chromosome immunostaining pattern of HP1a and H3K9me2 after CDK12 knockdown in our initial cytological observations, which show that CDK12 depletion induce heterochromatin spreading on euchromatic arms, especially on the X chromosome. This study describes a novel role of the CDK12 complex in controlling the epigenetic transition between euchromatin and heterochromatin. Examination of the genome-wide H3K9me2 and HP1a binding profile in wildtype larvae (WT) and CDK12-depleted larvae (CDK12-KD). Examination of the genome-wide CDK12 binding profile in wildtype larvae (WT). Twelve independent immunoprecipitations were conducted for each antibody. Two biological replicates were performed.
2015-11-02 | E-GEOD-63011 | biostudies-arrayexpress
Project description:The cyclin-dependent kinase CDK12 promotes transcription completion of long genes by suppressing the utilization of intronic polyadenylation sites that cause premature transcriptional termination. One class of genes that are particularly affected by loss of CDK12 activity are DNA damage response genes and therefore inhibitors of CDK12 have garnered interest as cancer therapeutic amplifiers. In this study, we used the CDK12/13 inhibitor THZ531 to treat HF1 (normal human fibroblasts), K562 and HeLa cells and the adenine analog 1-NM-PP1 to treat analog-sensitive HeLa cells and to assess the acute effects on transcription and RNA processing using Bru-seq and BruChase-seq. While acute transcriptional changes were small and limited to the 3’-ends of genes, RNA turnover was dramatically affected by CDK12 inhibition. Importantly, the downregulation of DNA damage response genes was predominantly due to increased mRNA turnover. Co-transcriptional splicing was suppressed by CDK12 inhibition. Finally, many introns that showed premature transcriptional termination were found to be resistant to degradation following CDK12 inhibition despite showing efficient splicing. We speculate that premature termination and addition of poly(A)s protect these spliced intronic fragments from degradation. These studies reveal previously unknown roles of CDK12 in regulating RNA turnover and co-transcriptional splicing.
2022-09-17 | GSE191222 | GEO
Project description:Methods: U2OS mRNA profiles of control siRNA(siControl) and siCDK12 were generated by deep sequencing, in triplicate, using Illumina. The sequence reads that passed quality filters were analyzed at the transcript isoform level. Total RNA-Seq was used for normalzation of RIP-Seq signals.Results: We report the application of RNA-immunoprecipitation-based sequencing for high-throughput profiling of mRNA abundence in mammalian cells. We generated genome-wide views of translation rate in CDK12-depleted U2OS cells in comparion to mTOR inhibitor, rapamycin treatment. We find that significant overlap and high corelation of change in eIF4G-associated mRNAs between two condition, rapamycin treatment and siCDK12 transfected cells. This study provides a role of CDK12 in translation control of mammalian cell.
2019-06-12 | GSE121391 | GEO
Project description:Methods: U2OS mRNA profiles of control siRNA(siControl) and siCDK12 were generated by deep sequencing, in triplicate, using Illumina. The sequence reads that passed quality filters were analyzed at the transcript isoform level. Total RNA-Seq was used for normalzation of RIP-Seq signals. Results: We report the application of RNA-immunoprecipitation-based sequencing for high-throughput profiling of mRNA abundence in mammalian cells. We generated genome-wide views of translation rate in CDK12-depleted U2OS cells in comparion to mTOR inhibitor, rapamycin treatment. We find that significant overlap and high corelation of change in eIF4G-associated mRNAs between two condition, rapamycin treatment and siCDK12 transfected cells. This study provides a role of CDK12 in translation control of mammalian cell.
2019-06-12 | GSE121390 | GEO